Plastic and reconstructive surgeons have long sought to develop a safe, predictable, and injectable material for soft tissue volume replacement. Surgeons seek not just to add bulk, but also to restore normal tissue consistency and composition. At present, injectable implant material can be designed to be tolerated by the host and to mimic the tissue it is designed to replace or augment. Even the well-tolerated implant, however, still acts as a foreign body after placement. A layer of host proteins rapidly adsorbs onto the hydrophobic implant surface of most polymers and attempts to degrade the polymer. The denatured proteins elicit an acute inflammatory response from the patient, attracting neutrophils, macrophages, and fibroblasts. Collagen is then deposited over the matrix on the implant, laying the groundwork for subsequent cellular adhesion. The degree of chronic inflammation that persists depends upon the specific qualities of the implant, as well as the local tissue environment.
Implant materials that undergo enzymatic degradation, nonspecific hydrolysis, or stress fragmentation will release breakdown products into the local environment. Local macrophages will generally engulf those particles that are 60 microns or smaller and may transport them to regional lymph nodes. Submicrometer-sized particles are the most easily transported and may remain intracellularly indefinitely. Particles ranging from 20 to 60 microns approach the size of a macrophage and may cause the death of the cell when engulfed. The dead cell then releases its intracellular enzymes, such as cytokines, which then attract more phagocytes. While destroying and engulfing the cellular debris, the phagocytes again encounter the polymer particles, and the cycle continues as a chronic inflammatory response. Many of the following injectable materials have tried to prevent such problems from occurring, but none of the currently available materials have been successful.
Injectable Biologic Material
Bovine collagen and its use as an injectable implant was first developed by Collagen Corporation in 1975 and called ZYDERM™. Bovine collagen is not desirable in facial plastic and reconstructive surgery because most users of ZYPLAST™, another bovine collagen product, describe a clinical effect of merely three to four months, while ZYDERM™'s results were even more short lived.
Mentor Corporation developed another product, FIBREL™, in attempt to simulate the process of wound healing. FIBREL™', which consists of plasma mixed with porcine-derived gelatin and e-aminocaproic acid (e-ACA), is injected intradermally. The plasma serves as a source of fibrin and clotting factors, the gelatin defines the site of the reaction, and the e-ACA limits fibrinolysis. The tissue reaction that occurs upon injection leads to fibrinogen deposition, followed by fibrinolysis and collagen formation. A disadvantage of FIBREL™ is that “touchups” are frequently required. Each of these collagen derivatives, (ZYDERM™, ZYPLAST™, and FIBREL™) are poorly suited for soft tissue augmentation because they rapidly biodegrade, and therefore, their effect is only transitory.
In order to fulfill the need for a natural, nonimmunogenic biologic material that can be produced in mass quantities, both Hylaform/Biomatrix and Q-med Uppsala developed derivatives of hyaluronic acid to be used as injectable soft tissue builders. These products are currently being evaluated by the FDA. Hylaform's HYLAN B gel product is an insoluble derivative produced by treating hyaluronic acid with vinyl sulfone. Q-Med Uppsala's RESTYLANE™ product also consists of hyaluronic acid but is cross-linked and processed into a 2% gel. Hyaluronic acid is a polysaccharide that plays an integral role in stabilizing the extracellular matrix, as well as lubricating, hydrating, and increasing its viscoelastic properties. Because hyaluronic acid is not species-specific, it does not elicit a humoral or cell-mediated immune response in the patient. The use of hyaluronic acid as an injectable filler results in greater than 33% improvement at 18 weeks.
Injectable Homologous Material
Collagenesis, Inc. developed the use of DERMALOGEN™, homologous collagen dispersion, which is well tolerated and elicits only a low grade inflammatory response. DERMALOGEN™ is a suspension of processed dermis obtained from AATB-accredited tissue banks. A mechanical process homogenizes the decellularized dermis to produce a suspension of mostly type I collagen, with trace amounts of types III and IV collagen, elastin, fibronectin, chondroitin sulfate, and other proteoglycans.
Similarly, LifeCell Corporation developed a product, ALLODERM™, that is an acellular sheet of meshed dermal proteins prepared from cadaver skin. Surgeons use this material for soft tissue augmentation in a variety of situations. An advantage of this material is that its effect is somewhat long term, lasting greater than one year. A distinct disadvantage is that use of this material requires an incision. Trials of long term efficacy will soon conclude for an injectable form of this material developed by the manufacturer. The injectable form consists of micronized ALLODERM™ particles ranging in size from 60 to 600 microns and is injected into a deep dermal level with a 26 gauge needle.
Injectable Autologous Material
Neuber first reported the use of fat transplantation in 1893, however, lipoaugmentation has several distinct disadvantages. The utility of fat transplantation is questionable because most of the transplanted materials do not survive. Reinjected autologous fat is known to have a resorption rate of approximately 70%, making repeated injections necessary. The ultimate result with fat transplantation depends upon the fibrotic reaction and the necrosis of the reinjected fat.
Isolagen Technologies attempts to enhance production of collagen with its ISOLAGEN™ product, by directly introducing cultured autologous fibroblasts. After a skin biopsy, autologous fibroblasts are isolated and expanded in vitro. A suspension of these fibroblasts is injected into the dermis and has been shown to provide persistent soft tissue augmentation. West and Alster treated eleven patients with ISOLAGEN™ and noted persistent correction in the nasolabial folds six months after the injection. In addition, Watson et al. found that injected fibroblasts seemed to be incorporated into the dermis and lead to new collagen production. Subjective improvement of the treated areas increased over a six month followup, however, widespread use of this product will depend on more long term results.
Injectable Synthetic Material
Lemperle et al. described results with ARTEPLAST™, a product developed by Rofil Medical International BV. ARTEPLAST™ is an injectable material composed of microspheres of polymethylmethylacrylate (PMMA) suspended in a gelatin solution. Following implantation, the gelatin is resorbed and replaced by native collagen.
ARTECOLL™ is a product, currently available in Europe and Canada, that the FDA is considering for use in the United States. ARTECOLL™ consists of smooth 30 to 40 micron PMMA spheres, suspended in bovine collagen from a closed pharmaceutical herd at a concentration of 25% PMMA, 75% collagen, by weight with 0.3% lidocaine. Because ARTECOLL™ contains bovine collagen, skin testing for allergy to bovine collagen is recommended. Although the PMMA beads averaged 30 to 40 microns in size, and are thus theoretically subject to phagocytosis by macrophages, no phagocytosis of PMMA spheres was detected.
Silicone injection into facial soft tissues became popular during the 1960's and 1970's, due to Dow Corning's introduction of medical grade silicone (MDX 4-4011). Silicone appears to be tolerated when in small amounts in the face and can be injected interdermally or subcutaneously. Microdroplets of silicone are dispersed within dermal tissues and are individually surrounded by foreign body reactions. Fibrosis around these droplets localizes the material, but a low grade inflammatory process remains.
A distinct drawback of injectable liquid silicone (350 cS viscosity) is that particles may migrate if the silicone is used in large quantities. Silicone particles have been found in the liver, brain, lungs, and kidneys. Injection of small quantities of medical silicone, less than two milliliters, is successful and safe for the treatment of hemifacial atrophy and other tissue deficiencies of the face. However, liquid silicone used in large doses can provoke serious general complications due to the migration of the particles.
Another injectable synthetic material is TEFLON™, produced by Dupont. TEFLON™ is inappropriate for usage in the face because migration of small particles of TEFLON™ paste and solid TEFLON have been reported.
Bioplastique™
Uroplasty BV designed BIOPLASTIQUE™, a biphasic material, consisting of solid silicone particles, ranging from 100 to 400 microns in size, suspended in a polyvinylpyrridolone ((C6H9NO)n) carrier (PVP). Bioplastique elicits a low-grade inflammatory response upon injection. In a rabbit model, the hydrogel carrier is reabsorbed by the body within 96 hours and renally eliminated in an intact form.
The hydrogel carrier is replaced by fibrin and inflammatory cells. Fibroblasts are recruited into the area by 14 days and begin to replace the fibrin bed with a collagen matrix. The collagen encapsulates and localizes the silicone, and animal studies have not shown any evidence of foreign body migration. Deposition of collagen progresses, replacing the organic component of the material in a ratio slightly greater than 1:1. Connective tissue cells develop and replace about 30% of the matrix with host collagen fibrils. At day 382 after injection, fibrosis was complete, and each individual BIOPLASTIQUE™ microimplant particle appeared to be encased in its own fibrous capsule.
Animal studies showed that BIOPLASTIQUE™ is very stable. Neither histologic examination of the regional lymph nodes at the base of the rabbit ears or cross-sections of the ear below the injected area showed microimplant particles in any of the rabbits under study.
The gel phase of the biphasic BIOPLASTIQUE™ is PVP, a member of the plasdone family. The gel is scavenged by the reticuloendothelial system and excreted unchanged by the kidneys within a matter of days. The PVP used in BIOPLASTIQUE has a molecular weight between 15,000 and 30,000 Da and has an appearance and consistency similar to that of honey. The plasdones have been used as vehicles and extenders for a variety of medications without negative effects for nearly fifty years.
BIOPLASTIQUE™ is generally implanted through a blunt, 20 gauge cannula and remains where it is placed. Complications may arise when too much material is placed in the skin or if the material is placed too close to the skin surface. BIOPLASTIQUE™ should only be used deep under the skin and never in the skin. BIOPLASTIQUE™ currently does not have FDA approval, but the manufacturer is evaluating an identical product, Macroplastique, for urethral incontinence under an FDA investigational drug exemption.
BIOPLASTIQUE™ has the distinct disadvantage of using silicone as the solid substrate. The solid phase of BIOPLASTIQUE™ is fully polymerized and vulcanized methyl methylpolysiloxane [(CH2)2—SiO]. Questions exist about the long-term safety of silicone materials.
Though many options exist for augmentation materials and methods, none of them are provide adequate augmentation. Therefore, what is needed are methods and compositions comprising safe, predictable, and solid injectable materials for tissue augmentation.